Autism spectrum disorders (ASD) are a group of neuropsychiatric conditions characterized by impairment in the ability to communicate, form relationships, and respond appropriately to the environment. With many autistic individuals having some degree of mental retardation, and most requiring lifelong assistance, the financial costs to society are very high, while the emotional and psychological costs to families cannot even be estimated. The high heritability of autism underscores important roles for inherited genetic variation, making possible (a) the use of genetic mapping to discover the pathways and processes that are causal for disease in the human population, and (b) the development of improved clinical prediction and more efficient use of interventions based on a complete understanding of the relationship between genotype and phenotype. Previous approaches to autism genetics have each led to the discovery of specific genes, mutations and biological mechanisms that play a role in autism. Many autism genes discovered so far are involved in plastic processes by which patterns of neuronal activity regulate the efficacy of the synaptic connections between neurons, and this synaptic plasticity is the molecular correlate of learning and memory. Yet in sum, the genes identified still leave unexplained the vast majority of the heritability of autism in humans - and, presumably, important etiological mechanisms that might (if known) productively guide development and deployment of therapy and prevention. The goal of this proposal is to bring together the power of 1) whole exome and genome sequencing, 2) homozygosity mapping in consanguineous families, 3) genome-wide maps of neuronal transcription in response to neuronal activity, and 4) genome-wide maps of the binding sites of factors that regulate this transcription to generate and annotate a catalog of ASD-associated variants. The consanguineous families are already enrolled in research, and have been phenotyped. The neuronal transcription and binding site maps will be developed by the Greenberg Lab at Harvard Medical School. The whole exome and whole genome sequencing will be done at the Broad Institute. And the Walsh lab at Children's Hospital will validate the results and analyze the variant data. This proposal will generate and make publicly available: Exomic sequence data and a catalog of variants in 85 consanguineous individuals diagnosed with ASD, Genomic sequence data and a catalog of variants in 35 consanguineous individuals diagnosed with ASD, Computational pipelines for analysis of next generation sequencing data Genome-wide map of coding and noncoding RNAs and alternative transcripts in resting and depolarized human neurons, Genome-wide map of binding sites for six activity-induced transcription factors (e.g. MEF2, c-fos, SR, CREB, CBP, etc.) in resting and depolarized human neurons, Results of validation analysis of rare variants associated with ASD. 1 PUBLIC HEALTH RELEVANCE: Autism and autism spectrum disorders are a group of neurological conditions characterized by impairment in the ability to communicate, form relationships, and respond appropriately to the environment. The discovery of genes that contribute to autism is critical not only for earlier and better diagnosis but also for informing strategies for prevention and therapy. This proposal aims to use the latest technologies to significantly increase our knowledge of the genetic causes of autism.